Dissecting aneurysm of aorta in rats fed with cysteamine.

Degeneration of elastic fibres leading to aortic aneurysm and rupture was observed in rats treated with cysteamine. The destructive changes are comparable to those of spontaneously occurring cardiovascular abnormalities in man.     

Collagenase inhibition in colonic mucosa by proteinase inhibitors

The effect of proteinase inhibitors on collagenase activity in rabbit colonic mucosa, both in vitro and in vivo, has been measured by a tissue culture method. Aprotinin, when applied to colonic explants at doses of 20 and 40 KIU, significantly reduced the lytic activity by 97.3% and 99.1% respectively (P less than 0.001). At doses of 100, 200 and 400 KIUs, lysis was completely abolished. Rectal biopsies taken from rabbits at 4, 24, 48 and 72 h following either intramuscular, oral or rectal administration of soy or lima bean trypsin inhibitor showed significant reductions in collagenolytic activity (P less than 0.001). The effects were greater and more rapid by the enteral routes of administration and the lima bean trypsin inhibitor was more effective than that of soy bean. The results suggest an inhibitory effect on collagenase by local lumenal action on colonic mucosa. Proteinase inhibitors may thus have a role to play in colorectal surgery by reducing collagen breakdown and increasing the strength of the healing anastomosis.     

Tape-strip sampling for measuring dermal exposure to 1,6-hexamethylene diisocyanate

OBJECTIVES: This study describes the development and evaluation of a method for sampling layers of the stratum corneum for the quantitation of dermal exposure to 1,6-hexamethylene diisocyanate (HDI). METHODS: HDI deposited on skin was collected by the removal of stratum corneum with adhesive tape, derivatized with 1-(2-methoxyphenyl)piperazine, and quantitated as the urea derivative (HDIU) by liquid chromatography-mass spectrometry (LC-MS). This LC-MS method was tested by analyzing tape spiked with HDI-containing products, then applied to tape samples collected from the skin of an auto-body shop worker exposed to polyurethane paint aerosols. RESULTS: The limits of detection and quantitation were 20 and 50 fmol per injection, respectively. The recovery of HDI from the tape was 99.3% [95% confidence interval (95% CI) 97.1-102]. HDIU was stable at -40 degrees C, degrading by 0.28% (95% CI 0.10-0.46) per day. Quantifiable amounts of HDI were observed in 42.6% of the first three successive tape-strip samples collected from 36 different sites on the skin of the worker. The amount of HDI recovered from the collection sites on skin, measured by summing the levels collected with three successive tape-strips, ranged from nondetectable to 1874 pmol. CONCLUSIONS: This study demonstrates that HDI on skin can be collected with tape-strips and quantified at occupational levels using LC-MS.     

Sudden cardiac death and the role of device therapy in dilated cardiomyopathy

Both nonischemic and ischemic dilated cardiomyopathy are associated with an increased risk of sudden cardiac death, most commonly as a result of ventricular tachyarrhythmias. The pathophysiology of sudden death is complex and results from the interplay of scarred myocardium with physiologic and environmental triggers. Clinical trials completed within the past decade have clarified the role of implantable defibrillators in prolonging survival and have expanded the indications for the use of these devices in patients with heart failure. This article examines the pathophysiology of sudden cardiac death and reviews the clinical trials that have defined the role of device therapy in current practice.     

A Rational Approach to Drug Development: The Confirmatory Phase

A rational approach to drug development would be model-based, target label and knowledge driven where the objective is to characterize the response surface – the interplay of drug regimen/exposure, and patient factors to elicit response (efficacy/safety) – that would result in the right dose for the right patient at the time of marketing the drug. This implies using population PK/PD, knowledge discovery and creation approaches, clinical trial simulation, appropriate surrogate/clinical endpoints, and appropriate statistical analysis for the characterization of the response surface. It also implies interacting with regulatory authorities prior to the initiation of clinical development and throughout the phases of clinical development to ensure that appropriate data to support a new drug application are being generated. To enable further characterization of the response surface in the later phases of development (i.e. phase IIb and beyond) and registration, the confirm–learn aspect of the learn–confirm–learn paradigm of drug development is advocated as the basis for answering the crucial drug development questions – “Is the NCE tolerated and at what dose range?” and “Does it work within the tolerated dose range?”